DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election with traverse of vorinostat as species i and 225-labled HuM195 as species ii in the reply filed on 3/26/2026 is acknowledged. The traversal is on the ground(s) that the inventive concept unifying all pending claims is the synergistic therapeutic combination of an epigenetic therapy agent - specifically, an HDAC inhibitor and/or LSD1 inhibitor - with a radioisotope-labeled targeting agent for the treatment of cancer. The pending claims collectively disclose and claim methods of treating cancer or inducing the death of cancer cells by administering or contacting those cells with: (i) one or both of an HDAC inhibitor and an LSD1 inhibitor, and (ii) a radioisotope-labeled agent that targets cancer cells in the subject, wherein the amounts of each component, when used in conjunction with one another, are therapeutically effective. This unified therapeutic approach - the combination of epigenetic modulation via HDAC or LSD1 inhibition with targeted radiotherapy - constitutes the special technical feature that provides the inventive contribution over the prior art.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that within each of the asserted classes epigenetic therapy agent and radioisotope-labeled targeting agent are an almost unlimited number of potential species which are potentially non-overlapping in scope and necessitate multiple search strategies and queries. For example, a prior art reference directed to an HDAC inhibitor is not necessarily applicable as prior art against claims directed to a LSD1 inhibitor, in addition to an almost unlimited number of potential radiolabeled compounds. The requirement is still deemed proper and is therefore made FINAL.
Claims 2-4, 6, 7, 10, 13-17, 19, 21, 24-28, 30, 31, 34 and 35 are pending, of which claims 3, 31, 34 and 35 are withdrawn as being directed to non-elected species. Claims 2, 4, 6, 7, 10, 13-17, 19, 21, 24-28 and 30 encompass the elected species and are examined herein on the merits for patentability.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
The following reference was found during the search for the elected species and is provided in the interest of compact prosecution. It should not be interpreted that a comprehensive search was performed for all non-elected species.
Claim(s) 2, 4, 6, 7, 17, 19, 24 and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dubois et al. (Clin Cancer Res; 2015, 21(12), 2715-2721).
Dubois discloses that 131I-metaiodobenzylguanidine (MIBG) is a radio pharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase I study was to determine the MTDs of vorinostat and MIBG in combination.
Patients ≤30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily days 1 to 14. MIBG (dose levels 8,12,15, and 18mCi/kg) was given on day 3 and peripheral blood stem cells on day 17. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on days 3 and 12 to 14. In conclusion vorinostat at 180 mg/m2 / dose is tolerable with 18 mCi/kg MIBG.
Claim(s) 2, 4, 6, 7, 10, 17, 19, 21, 24 and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hodge (US 2019/0183870).
Hodge discloses a method of reducing cancer cell growth, which method comprises treating cancer cells with a combination of a histone deacetylase (HDAC) inhibitor and immunotherapy, whereupon growth of the cancer cells is reduced. The cancer cells include prostate cancer cells, breast cancer cells, lung cancer cells, or colon cancer cells. The HDAC inhibitor is vorinostat (claims 1-7). The cancer may be acute myeloblastic leukemia or multiple myeloma (paragraph 0023). The immunotherapy includes a radiopharmaceutical; radium-223 (XOFIGO) (claims 9 and 16). The cancer cells are in vitro or in vivo, including human (claims 19-21).
The combination of a HDAC inhibitor and immunotherapeutic agent (e.g., cancer vaccine) can be administered sequentially or simultaneously. In certain embodiments, one or more (e.g., 2, 3, 4, or 5) HDAC inhibitors is administered in combination with one or more (e.g., 2, 3, 4, or 5) immunotherapeutic agents (paragraph 0046).
Claim(s) 2, 4, 6, 7, 10, 13-17, 19, 21, 24-28 and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sgouros (US 2009/0054720).
Sgourous discloses that histone deacetylase (HDAC) inhibitors, such as SAHA can be used in combination with a radiation source such as external beam irradiation or a radioisotope, such as a radiopharmaceutical, to provide therapeutically effective anticancer effects. Furthermore, an unexpected synergistic interaction between the HDAC inhibitor and the radiation source results in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect resulting from administration of the two treatments each at a therapeutic dose. These observations suggest that HDAC inhibitors, such as SAHA, can act as radiosensitizers that can be used in combination with radiotherapy for the treatment of cancer. (paragraph 0010). It is noted that SAHA is synonymous with vorinostat.
The combination therapy of the present invention is suitable for use in the treatment of a wide variety of cancers. As used herein, cancer refers to tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. For example, cancers include, but are not limited to, leukemias and lymphomas such as cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphomas associated with human T-cell lymphotropic virus (HTLV), for example, adult T-cell leukemia/lymphoma (ATLL), acute lymphocytic leukemia, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease, non-Hodgkin's lymphomas, and multiple myeloma, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' Tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon), lung cancer, breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain cancer, liver cancer and thyroid cancer (paragraph 0056).
A "radiopharmaceutical agent" refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and/or therapy of various diseases. The radiolabelled pharmaceutical agent, for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source (paragraph 0147).
For alpha-emitting radiation, spheroids were exposed to a radioactivity concentration of (100 nCi/mL) of Ac225-HuM 195 alpha emitting radiation for 24 hours. Ac225-HuM 195 is a recombinant humanized Anti-CD33 monoclonal antibody which has been radiolabelled with actinium225 (paragraph 0194).
Combination studies with 24 hour exposure to Ac225-HuM195 followed by a 96 h incubation with 5 µM SAHA (also known as vorinostat) caused complete growth inhibition, which was maintained for a period of over 50 days (FIG. 8). In contrast, Ac225-HuM195 treatment alone did not cause growth inhibition of the spheroids, and a 96 h exposure to 5 µM SAHA alone yielded an initial 10 day delay, followed by spheroid growth to almost the levels of control untreated spheroid volume after a period of 30 days (paragraph 0220).
The combination of radiation and SAHA yielded growth suppression that led to 10- to 100-thousand-fold differences in spheroid volumes relative to each modality alone (paragraph 0221).
See also claims 44+ directed to treating brain cancer in a patient in need thereof comprising administering to said patient a first amount of a histone deacetylase (HDAC) inhibitor, wherein said histone deacetylase inhibitor is suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt thereof, and a second amount of radiation, wherein the first and second amounts together comprise a therapeutically effective amount.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 2, 4, 6, 7, 10, 13, 17, 19, 21, 24, 25 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Walter et al. (US 2016/0317657).
Walter teaches a pharmaceutical composition comprising a CD33 targeting compound and at least one epigenetic factor, wherein (a) the CD33 targeting compound is a bispecific construct comprising a first binding domain specifically binding to CD33 and a second binding domain specifically binding to CD3; and (b) the at least one epigenetic factor is selected from the group consisting of histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) I inhibitors, hydroxyurea, Granulocyte-Colony Stimulating Factor (G-CSF), histone methyltransferase (HMT) inhibitors and ATRA (All Trans-retinoic acid) (paragraph 0005).
The HDAC inhibitor includes vorinostat (paragraph 0008).
The invention also provides a pharmaceutical composition, wherein [0013] (a) the epigenetic factor is administered prior to the administration of the CD33 targeting compound; (b) the epigenetic factor is administered subsequent to the administration of the CD33 targeting compound; or (c) the epigenetic factor and the CD33 targeting compound are administered simultaneously (paragraph 0012).
The CD33 targeting compound is a bispecific antibody (paragraph 0017-21).
The pharmaceutical composition of the invention is envisaged for the treatment of CD33 expressing myeloid leukemia. Preferably, the myeloid leukemia is selected from the group consisting of acute myeloblastic leukemia (paragraph 0025).
It is also envisaged that the CD33 targeting compound described herein has, apart from its function to bind to the cell surface molecule CD33 on a target cell and CD3 on the cell surface of a T cell, may have an additional function. In this format, the compound is a multifunctional compound by targeting cells through binding to CD33 on the cell surface of a target cell, mediating cytotoxic T cell activity through CD3 binding and providing a further function such as a fully functional Fc constant domain mediating antibody-dependent cellular cytotoxicity through recruitment of effector cells like NK cells, a half life extending domain such as an albumin binding domain or a modified Fc constant domain lacking antibody-dependent cellular cytotoxicity but extending the molecular weight of the compound, mediation of a label (fluorescent etc.), a therapeutic agent such as, e.g. a toxin or radionuclide, and/or means to enhance serum half-life, etc. (paragraph 0138).
Walter does not specifically exemplify an embodiment wherein a radiolabeled CD33 targeting antibody is administered in combination with an HDAC inhibitor in a method of cancer treatment. However, it would have been obvious to one ordinary skill in the art at the time of the invention to provide a radionuclide labeled anti-CD33 because methods of treatment of various cancers including leukemia using a combination of an HDAC inhibitor (vorinostat) and a CD33 targeting antibody, and further teaches that the CD33 targeting compound may provide a further function, including a therapeutic radionuclide.
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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